The goal of this clinical trial is to test a compounded dimethyl sulfoxide (DMSO)-based dual-route therapy for adults with refractory subjective tinnitus linked to long-COVID (post-acute sequelae of SARS-CoV-2) or post-COVID-19 vaccine injury. Participants have bothersome tinnitus that has not improved with at least two prior standard treatments.

All participants will receive two study treatments for 30 days: a DMSO-based ear canal liquid and a DMSO-based transdermal cream applied to the skin around the ears and upper neck. The ear drops are used every 4 days, and the cream is applied once daily at bedtime. Both formulations are prepared by a licensed compounding pharmacy.

The main question is whether at least half of the participants achieve a 50% or greater reduction in their Tinnitus Handicap Inventory (THI) score from baseline to Day 30. Researchers will also look at changes in tinnitus loudness and annoyance, sleep and concentration, other symptoms such as vertigo, insomnia, headache, and fatigue, and any side effects.

After an initial in-person ear, nose, and throat (ENT) evaluation, all study visits are conducted by telemedicine. Participants complete electronic questionnaires through a secure, HIPAA-compliant system over 12 months of follow-up.

Subjective non-pulsatile tinnitus is a common and often debilitating symptom in patients with post-acute sequelae of SARS-CoV-2 (PASC, long-COVID) and post-COVID-19 vaccine injury. Mechanisms are thought to include neuroinflammation, microvascular dysfunction, oxidative stress, and mitochondrial impairment within cochlear and central auditory pathways. A substantial proportion of patients remain highly symptomatic despite standard therapies such as sound therapy, cognitive behavioral approaches, antidepressants, and corticosteroids. No FDA-approved curative pharmacologic therapy exists for chronic subjective tinnitus.

Dimethyl sulfoxide (DMSO) is a tree-derived solvent with anti-inflammatory, antioxidant, vasodilatory, and penetration-enhancing properties. A foundational open-label study in the 1970s reported that DMSO-based formulations combined with vasoactive and anti-inflammatory agents improved or resolved subjective tinnitus in most treated patients, but this approach has not been systematically evaluated in modern refractory PASC or vaccine-injury cohorts. This pilot trial modernizes that historical concept using current compounding standards and telemedicine-enabled follow-up.

This is a prospective, single-arm, open-label pilot study of approximately 20 adults with refractory subjective tinnitus attributed to PASC or post-COVID-19 vaccine injury. All participants receive a dual-route regimen for 30 days: (1) a DMSO-based otic liquid instilled into the external auditory canal every 4 days, and (2) a DMSO-based transdermal cream applied once daily to the bilateral mastoid regions, periauricular skin, and upper posterior neck. Both formulations are compounded by a licensed pharmacy according to protocol specifications. Standard tinnitus counseling and sound therapy are allowed, but no new tinnitus-specific medications may be started during the 30-day treatment window.

The primary objective is to estimate the proportion of participants achieving at least a 50% reduction in Tinnitus Handicap Inventory (THI) score from baseline to Day 30. Secondary objectives include changes in THI score at later time points, visual analog scale (VAS) ratings of tinnitus loudness, annoyance, sleep interference, and concentration, patient global impression of change, and VAS measures of concomitant symptoms such as vertigo, insomnia, headache, and fatigue. Safety and tolerability are assessed by monitoring adverse events, including expected DMSO-related effects such as transient odor or skin irritation. Exploratory measures may include changes in tympanic membrane temperature and audiometric parameters where available.

Screening and informed consent are performed via telemedicine, followed by a required baseline in-person ENT evaluation with otoscopy, audiometry, and completion of the THI and other questionnaires. During the 30-day treatment period, participants have regular telemedicine check-ins and complete electronic questionnaires through a secure, HIPAA-compliant REDCap-based platform. Follow-up assessments occur at approximately 6 and 12 months to evaluate durability of tinnitus response and longer-term safety. As a pilot study, analyses are descriptive and use paired pre- and post-treatment comparisons to generate effect-size estimates and feasibility data for future controlled trials.

Inclusion Criteria:

• Inclusion Criteria:

Adults 18 to 70 years of age.

Chronic subjective non-pulsatile tinnitus for at least 6 months.

Bothersome tinnitus defined by a Tinnitus Handicap Inventory (THI) score ≥ 20 at screening.

Documented history of post-acute sequelae of SARS-CoV-2 (PASC, long COVID) or post-COVID-19 vaccine injury, with tinnitus onset or clear worsening temporally associated with that event.

Failure of at least two prior tinnitus therapies (for example, sound therapy, counseling or cognitive-behavioral approaches, pharmacologic treatments, or steroid therapy).

Willing and able to provide informed consent.

Able to complete telemedicine visits and electronic questionnaires in English and to attend a baseline in-person otolaryngology (ENT) evaluation.

Exclusion Criteria:

Objective or pulsatile tinnitus, or tinnitus primarily synchronous with the heartbeat.

Active middle-ear infection, acute otitis media, tympanic membrane perforation, or current otorrhea.

Recent exposure (within the past 3 months) to known ototoxic medications associated with new or rapidly worsening tinnitus.

Known hypersensitivity or allergy to dimethyl sulfoxide (DMSO) or any component of the study formulations (betahistine, dexamethasone, lidocaine, levocarnitine, N-acetylcysteine, or excipients).

Pregnancy or breastfeeding.

Uncontrolled or severe psychiatric illness (for example, active psychosis, acute suicidality) that, in the opinion of the investigator, would interfere with participation or completion of questionnaires.

Inability to comply with study procedures, including telemedicine visits, electronic data capture, or topical/otic dosing instructions.

Any other otologic or neurologic condition judged by the investigator to confound tinnitus assessment or pose unacceptable risk with DMSO-based therapy.

No individual participant data (IPD) will be shared. Aggregate study results may be published in scientific journals and presented at conferences.